CA1282703C - Stable injectable antiemetic compositions - Google Patents
Stable injectable antiemetic compositionsInfo
- Publication number
- CA1282703C CA1282703C CA000534087A CA534087A CA1282703C CA 1282703 C CA1282703 C CA 1282703C CA 000534087 A CA000534087 A CA 000534087A CA 534087 A CA534087 A CA 534087A CA 1282703 C CA1282703 C CA 1282703C
- Authority
- CA
- Canada
- Prior art keywords
- water
- composition
- glycerol
- solution
- formula
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
- Dermatology (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Abstract Stable, injectable, aqueous solutions of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(substituted)alkoxy]benzamide antiemetic agents are prepared by adding, as stabilizing agent, a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the polarity of the solution.
Description
2~(~3 STABLE_INJE~TABLE ANTIEMETIC COMPOSITIONS
summary of the Invention This invention relates to stable, injectable, aqueous solutions of 4-amino-~-chloro-N-[2-(diethylamino)ethyl3-2-[(substituted)alkoxy]benzamide antiemetic agents containing, as stabilizing agent, a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the polarity of the solution.
Backqround and DescriPtion of_the Prior Art Methods for the stabilization of medicaments vary widely, depending on the type of medicament. The addition of a reducing agent to an easily oxidized medicament is a well-known example. Ascorbic acid has been stabilized against oxidation by the use of a mixed solvent having a decreased dissolved oxygen content. The degradation (by hydrolysis) of some anesthetic esters has been inhibited by the addition of caffeine, which was shown to complex with the esters. The series of "paraben" preservatives, e.g., methyl paraben, ethyl paraben, propyl paraben and butyl paraben, are well-known stabilizers used in numerous pharma-ceutical compositions. U.S. Patent 4,328,213, issued on May 4, 1982 to V. Ecker et al., for example, describes and claims their use in the stabilization of injectable labetalol formulations.
The antiemetic agents utilized in the stable formu-lations described and claimed herein are known compounds, having been described, for example, in published U.K. Patent 2~03 Application 2,160,871 A, published January 2, 1986.
Metoclopramide is a well-known antiemetic agent with a structure similar to the antiemetic agents utilized herein, e~cept that it contains a methoxy group in the 2-position.
The Physicians' Desk Reference, 36th edition, 1982, pages 186~-6, shows that the injectable form of metoclopramide sold at that time was stabilized with sodium metabisulfite.
Published U.K. Patent Application 2,158,714 A, pub-lished November 20, 1985, confirms that injectable metoclo-pramide formulations were then stabilized wLth sodium metabisulfite. It goes on to point out that metoclopramide was being used in conjunction with cisplatinum chemotherapy for cancer, and that cisplatinum had been found to be incompatible with sodium metabisulfite. It states that it was found that, surprisingly, sodium metabisulfite could be eliminated from injectable metoclopramide formulations without unduly affecting their stability.
In Chem. Pharm. Bull., 8, 504 (1960), K. Ikeda reports the results of a study which showed increased stability of certain barbiturates in water-ethanol or water-methanol solutions having reduced dielectric constants, as compared with aqueous solutions of the barbiturates.
In Chem. Pharm. Bull., 8, (1960), K. Ikeda reports that the same barbiturates have increased stability in aqueous solutions of ethylene glycol, propylene glycol, glycerol, glucose, mannitol and sucrose. However, his studies showed that the stabilization could not be attributed only to the change of dielectric constant of the medium. Moreover, he refers to the work of E.S. Amis et al. in J. Am. Che~,. Soc., - . . .
63, 2621 (1940) with the alkaline degradation of bro~thymol blue. Amis et al. found that the reaction between negative bivalent dye ion and hydroxyl ion was in accordance with the theory in methanol-water and ethanol-water, but in glycerol-water mixture the activation energy was opposite to the theory on dielectric constant.
In J. Am. Pharm. Assoc , 48, 77 (1959), A.D~ Marcus et al. refer to "the widespread use of mixed solvents in pharmaceuticals and the relative lack of information concerning the effects of such solvent systems upon the stability of the active ingredients". They point out that any assumption that replacement of part of the water by a non-aqueous solvent is some sort of a panacea is erroneous, and probably results from a lack of appreciation of the ability of non-aqueous solvents, especially those which are hydroxylic, to participate in, or otherwise influence, solvolytic reactions. In a study of the hydrogen ion catalyzed solvolysis of chloramphenicol in water-propylene glycol solutions, they found that the addition of propylene glycol to the aqueous solution increased the rate of solvolysis of the chloramphenicol.
Complete Disclosure This invention relates to stable, injectable, aqueous solutions of antiemetic agents having the Formula I
CH3CH2 ~
CH3CH2 ~NCR2cH2HNo Rlo ~3 ~ ~ R2 14 Cl NH~
wherein Rl, R2 and R3 each are independently hydrogen or methyl, and R4 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or, when R3 is hydrogen, R4 may be phenyl, or a nontoxic, pharmaceuti-cally acceptable acid addition salt thereof, containing as stabilizing agent a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the polarity (dielectric constant) of the solution. Preferred organic hydroxylic stabilizers include ethanol, propylene glycol glycerol and mannitol, with glycerol being the most preferred. A particularly preferred pharmaceutically acceptable acid addition salt of a compound of Formula I is the hydrochloride. The most preferred compound of Formula I
is the compound wherein Rl, R3 and R4 are hydrogen, and R2 is methyl, which is named 4-amino-2-(2-butanon-3-yl)-oxy-5-chloro-N-{2-(diethylamino)ethyl]benzamide (Ia).
The compounds of Formula I in aqueous, isotonic (isotonicity adjusted with sodium chloride and/or dextrose) and buffered (O.lM citrate and phosphate buffers, pH 5.7 and 6.5) formulations containing the equivalent of 5 mg of free base of a compound of Formula I per ml have been found unsuitable for long term shelf life. Typical isotonic and .. . .
'.
~2703 buffered formulations lost 33% and 40%, respectively, of their potency following storage far eight weeks at 56C.
The compound of Formula Ia, for example, has been found to degrade via an intramolecular cyclization reaction leading to the formation of the compound of Formula II
C~3C~2 C~l CE~ ~N 2C~2HNC
summary of the Invention This invention relates to stable, injectable, aqueous solutions of 4-amino-~-chloro-N-[2-(diethylamino)ethyl3-2-[(substituted)alkoxy]benzamide antiemetic agents containing, as stabilizing agent, a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the polarity of the solution.
Backqround and DescriPtion of_the Prior Art Methods for the stabilization of medicaments vary widely, depending on the type of medicament. The addition of a reducing agent to an easily oxidized medicament is a well-known example. Ascorbic acid has been stabilized against oxidation by the use of a mixed solvent having a decreased dissolved oxygen content. The degradation (by hydrolysis) of some anesthetic esters has been inhibited by the addition of caffeine, which was shown to complex with the esters. The series of "paraben" preservatives, e.g., methyl paraben, ethyl paraben, propyl paraben and butyl paraben, are well-known stabilizers used in numerous pharma-ceutical compositions. U.S. Patent 4,328,213, issued on May 4, 1982 to V. Ecker et al., for example, describes and claims their use in the stabilization of injectable labetalol formulations.
The antiemetic agents utilized in the stable formu-lations described and claimed herein are known compounds, having been described, for example, in published U.K. Patent 2~03 Application 2,160,871 A, published January 2, 1986.
Metoclopramide is a well-known antiemetic agent with a structure similar to the antiemetic agents utilized herein, e~cept that it contains a methoxy group in the 2-position.
The Physicians' Desk Reference, 36th edition, 1982, pages 186~-6, shows that the injectable form of metoclopramide sold at that time was stabilized with sodium metabisulfite.
Published U.K. Patent Application 2,158,714 A, pub-lished November 20, 1985, confirms that injectable metoclo-pramide formulations were then stabilized wLth sodium metabisulfite. It goes on to point out that metoclopramide was being used in conjunction with cisplatinum chemotherapy for cancer, and that cisplatinum had been found to be incompatible with sodium metabisulfite. It states that it was found that, surprisingly, sodium metabisulfite could be eliminated from injectable metoclopramide formulations without unduly affecting their stability.
In Chem. Pharm. Bull., 8, 504 (1960), K. Ikeda reports the results of a study which showed increased stability of certain barbiturates in water-ethanol or water-methanol solutions having reduced dielectric constants, as compared with aqueous solutions of the barbiturates.
In Chem. Pharm. Bull., 8, (1960), K. Ikeda reports that the same barbiturates have increased stability in aqueous solutions of ethylene glycol, propylene glycol, glycerol, glucose, mannitol and sucrose. However, his studies showed that the stabilization could not be attributed only to the change of dielectric constant of the medium. Moreover, he refers to the work of E.S. Amis et al. in J. Am. Che~,. Soc., - . . .
63, 2621 (1940) with the alkaline degradation of bro~thymol blue. Amis et al. found that the reaction between negative bivalent dye ion and hydroxyl ion was in accordance with the theory in methanol-water and ethanol-water, but in glycerol-water mixture the activation energy was opposite to the theory on dielectric constant.
In J. Am. Pharm. Assoc , 48, 77 (1959), A.D~ Marcus et al. refer to "the widespread use of mixed solvents in pharmaceuticals and the relative lack of information concerning the effects of such solvent systems upon the stability of the active ingredients". They point out that any assumption that replacement of part of the water by a non-aqueous solvent is some sort of a panacea is erroneous, and probably results from a lack of appreciation of the ability of non-aqueous solvents, especially those which are hydroxylic, to participate in, or otherwise influence, solvolytic reactions. In a study of the hydrogen ion catalyzed solvolysis of chloramphenicol in water-propylene glycol solutions, they found that the addition of propylene glycol to the aqueous solution increased the rate of solvolysis of the chloramphenicol.
Complete Disclosure This invention relates to stable, injectable, aqueous solutions of antiemetic agents having the Formula I
CH3CH2 ~
CH3CH2 ~NCR2cH2HNo Rlo ~3 ~ ~ R2 14 Cl NH~
wherein Rl, R2 and R3 each are independently hydrogen or methyl, and R4 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or, when R3 is hydrogen, R4 may be phenyl, or a nontoxic, pharmaceuti-cally acceptable acid addition salt thereof, containing as stabilizing agent a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the polarity (dielectric constant) of the solution. Preferred organic hydroxylic stabilizers include ethanol, propylene glycol glycerol and mannitol, with glycerol being the most preferred. A particularly preferred pharmaceutically acceptable acid addition salt of a compound of Formula I is the hydrochloride. The most preferred compound of Formula I
is the compound wherein Rl, R3 and R4 are hydrogen, and R2 is methyl, which is named 4-amino-2-(2-butanon-3-yl)-oxy-5-chloro-N-{2-(diethylamino)ethyl]benzamide (Ia).
The compounds of Formula I in aqueous, isotonic (isotonicity adjusted with sodium chloride and/or dextrose) and buffered (O.lM citrate and phosphate buffers, pH 5.7 and 6.5) formulations containing the equivalent of 5 mg of free base of a compound of Formula I per ml have been found unsuitable for long term shelf life. Typical isotonic and .. . .
'.
~2703 buffered formulations lost 33% and 40%, respectively, of their potency following storage far eight weeks at 56C.
The compound of Formula Ia, for example, has been found to degrade via an intramolecular cyclization reaction leading to the formation of the compound of Formula II
C~3C~2 C~l CE~ ~N 2C~2HNC
3 2 Cl ~ C~3 II
which was isolated and identified. Tables 1 and 2 give the results of stability tests on the compound of Formula Ia in water and in isotonic saline, and in citrate buffers, respectively.
1~27~3 Table 1 Stability of ComPound Ia (5m~ in Water and Isotonic Saline at 56C_ Time % Remaining(a) % Remaining(a) (Weeks)(Water) (Isotonic Saline) Initial 100.0 100.0 1 97.4 96.0 2 95.5 91.6 4 90.8 83.5 8 80.5 66.9 (a) Reported values are the average of duplicate samples.
Table 2 StabilitY of ComPound Ia (5 mq/ml) in O.OlM Citrate ~uffers at pH 5.7 and 6.5 at 56C
Time % Remaining(a) % Remaining(a) (Weeks)(PH 5.7) (pH 6.5) Initial 100.0 100.0 1 94.8 93.6 2 87.8 87.9 4 77.2 77.5 8 58.9 60.3 (a) Reported values are the average of duplicate samples.
: ~ , 3L2E~2~3 According to the present invention it has been found that a stable, injectable, aqueous formulation of a compound of Formula I can be attained by the addition of a pharmaceutically acceptable hydroxylic organic solvent or water soluble polyhydric alcohol or sugar to lower the dielectric constant (polarity) of the solution. Preferred hydroxylic stabilizers include ethanol, propylene glycol, glycerol and mannitol with glycerol being the most preferred.
The amount of hydroxylic stabilizer to be added may vary from about 5% up to about 75% depending on the actual compound used. However, we prefer to use from about 5% to about 30%, and most preferably from about 10% to about 20%.
For example, we have found that compositions containing 75%
ethanol are among the most stable but, because of potential undesirable side effects from the intravenous administration of moderate amounts of ethanol, we prefer to use much lower amounts of ethanol or even to use a different hydroxylic solvent such as glycerol. Even glycerol, in high dosage may cause undesirable side effects and, for that reason, we most prefer to use the stabilizer at a concentration of about 10%.
The amount of Compound I per ml of stable formulation may vary from 1 mg to about 50 mg or even more, depending on the particular compound. We prefer to use at least 1 mg/ml and up to about 40 mg/ml.
The pH of the final composition should be in the range of from about 4 to about 7, and preferably is from about 5.0 to about 6.7. Most preferably, the pH is within the range of from about 6.0 to about 6.5.
~ 7 ~
Optionally, about 9 mg/ml of the preservative benzyl alcohol may be added to the formulation. This is partlcularly desirable if the formulation is packaged in multiple dose form.
The pharmaceutically acceptable acid addition salts of the compounds of Formula I may be derived from any of the acids commonly used in the pharmaceutical art. Preferred salts are the sulfate, maleate, tartrate, citrate and hydrochloride, with the hydrochloride being the most preferred.
The hydroxylic stabilizing compounds utilized herein, such as ethanol, propylene glycol, glycerol and mannitol, all lower the dielectric constant of the formulations.
Although we believe that the stabilizing effect is due, at least partially, to the lowered dielectric constant of the -formulations, we do not intend to limit ourselves to any particular theory.
The dosage of the compounds of Formula I depend on the particular active ingredient, the age, weight and general health of the patient, as well as the severity of the malady, and is within the discretion of the physician. For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapeutic agents, the compounds of Formula I are generally administered at a dosage of from about 1 mg/kg to about 50 mg/kg, given several times per day.
7~3 Example 1 Inqredient Amount/ml Compound Ia Hydrochloride 5.~ mg Glycerol 200 mg Sodlum Hydroxide (O.OlN) 65 ~1 Water for Injection q.s. ad 1.00 ml Procedure for Formulation Into a suitable çompounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approximately 70% of the batch volume of water in the compounding vessel. Quantitatively add the glycerol with continuous stirring until complete mixing is achieved.
Add the active ingredient and the sodium hydroxide solution~
Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
_ g _ ' ~q~
Example 2 In~redlent Amount/ml Compound Ia Hydrochloride 5.51 mg Propylene Glycol 200 mg Sodium Hydroxide ~O.01 N) 70 ~1 Water for Injection q.s. ad1.00 ml Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes, While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approxima~ely 70% of the batch volume of water in the compounding vessel. Quantitatively add the propylene glycol with continuous stirring until complete mixing is achieved. Add the active ingredient and the sodium hydroxide solution. Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 3-Ingredient Amount/ml Compound la Hydrochloride5.51 mg Ethyl Alcohol 200 mg Sodium Hydroxide (O.OlN) 55 ~1 Water for injecticn ~.s. ad 1.00 ml Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approximately 70% of the batch volume of water in the compounding vessel. Quantitatively add the ethyl alcohol with continuous stirring until complete mixing is achieved. Add the active ingredient and the sodium hydroxide solution. ~ring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 4 Ingredient Amount~ml Compound Ia Hydrochloride44.1 mg Glycerol 200 mg Sodium Hydroxide (O.OlN)to pH 6.0-6.2 Water for Injection q.s. ad 1.00 ml l~,tZ7~3 Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approximately 70% of the batch volume of water in the compounding vessel. Quantitatively add the glycerol with continuous stirring untll complete mixing is achieved. Add the active ingredient and the sodium hydroxide solution.
Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 5 Ingredient Amount/ml Compound Ia Hydrochloride 11.0 mg Glycerol 350 mg Sodium Hydroxide (O.OlN) to pH 6.0-6.2 Water for Injection q.s. ad 1.00 ml Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approxima~ely 70% of the batch volume of water in the compounding vessel. Quantitatively add the glycerol with continuous stirring until complete mixing is achieved.
27(~3 Add the active ingredient and the sodium hydroxide solution.
Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 6 Ingredient Amount/ml Compound Ia Hydrochloride 1.1025 mg Glycerol 100.0 mg Benzyl Alcohol 9.0 mg Sodium Hydroxide (l.ON) to pH 6.3+0.2 Water for Injection q.s. ad 1.00 ml Example 7 In~redient Amount/ml Compound Ia Hydrochloride 11.025 mg Glycerol 100.0 mg Benzyl Alcohol 9.0 mg Sodium Hydroxide (l.ON) to pH 6.3+0.2 Water for Injection q.s. ad 1.00 ml Example 8 Ingredient Amount/ml Compound Ia Hydrochloride 27.56 mg Glycerol 100.0 mg Benzyl ~lcohol .9.0 mg Sodium Hydroxide (l.ON) to pH 6.3+0.2 Water for Injection q.s. ad 1.00 ml Procedure_f r Formulation of ExamPles 6L 7 and 8 In a suitable vessel, collect 80% of the required amount of Water for Injection and overlay with nitrogen.
While stirring, add and dissolve the Glycerol, Benzyl Alcohol and Compound Ia. Agitate to ensure homogeniety and continuously overlay with Nitrogen NF. Adjust the pH of the solution to 6.3 ~ 0.2 by addition of lN Sodium Hydroxide Solution. Bring the solution to the desired batch volume with Water for Injection, and stir to ensure complete dissolution. Aseptically filter the solution using a sterilized membrane filter, and collect the filtrate in a sterilized receiving vessel. Fill the solution into sterilized ampules, overlay with nitrogen and seal the ampules.
Tables 3 and 4, below, provide stability data for some of the stable injectable formulations of the present invention.
Table 3 Stabilit~ of Com~ound Ia (5mq~ml) in Ethanol-Water Mixtures at 56C
Ethanol/Water Calculated % Remaining % Remaining ~v/v) Dielectric(4 weeks)(8 weeks) Constant .
0/100 78.5 94.9 89.4 25/75 64.9 98.7 97.-5 50/50 51.4 99.5 99.1 75/25 37.8 99.6 99.6 `
Table 4 Stability of ComPound Ia (5mg/ml) in Pro~Ylene Glvcol-Water and Glvcerol-Water at 56C
Solvent Calculated% Remaining %Remaining Dielectric (4 weeks)(8 weeks) Constant -Water 78.5 94.9 88.1 25% (w/v) 67.3 97.7 96.8 Propylene Glycol 5% (w/v) Glycerol 76.3 95.1 90.9 15% ~w/v) Glycerol 71.8 96.. 5 94.2 25% (w/v) Glycerol 71.4 96.8 95.3
which was isolated and identified. Tables 1 and 2 give the results of stability tests on the compound of Formula Ia in water and in isotonic saline, and in citrate buffers, respectively.
1~27~3 Table 1 Stability of ComPound Ia (5m~ in Water and Isotonic Saline at 56C_ Time % Remaining(a) % Remaining(a) (Weeks)(Water) (Isotonic Saline) Initial 100.0 100.0 1 97.4 96.0 2 95.5 91.6 4 90.8 83.5 8 80.5 66.9 (a) Reported values are the average of duplicate samples.
Table 2 StabilitY of ComPound Ia (5 mq/ml) in O.OlM Citrate ~uffers at pH 5.7 and 6.5 at 56C
Time % Remaining(a) % Remaining(a) (Weeks)(PH 5.7) (pH 6.5) Initial 100.0 100.0 1 94.8 93.6 2 87.8 87.9 4 77.2 77.5 8 58.9 60.3 (a) Reported values are the average of duplicate samples.
: ~ , 3L2E~2~3 According to the present invention it has been found that a stable, injectable, aqueous formulation of a compound of Formula I can be attained by the addition of a pharmaceutically acceptable hydroxylic organic solvent or water soluble polyhydric alcohol or sugar to lower the dielectric constant (polarity) of the solution. Preferred hydroxylic stabilizers include ethanol, propylene glycol, glycerol and mannitol with glycerol being the most preferred.
The amount of hydroxylic stabilizer to be added may vary from about 5% up to about 75% depending on the actual compound used. However, we prefer to use from about 5% to about 30%, and most preferably from about 10% to about 20%.
For example, we have found that compositions containing 75%
ethanol are among the most stable but, because of potential undesirable side effects from the intravenous administration of moderate amounts of ethanol, we prefer to use much lower amounts of ethanol or even to use a different hydroxylic solvent such as glycerol. Even glycerol, in high dosage may cause undesirable side effects and, for that reason, we most prefer to use the stabilizer at a concentration of about 10%.
The amount of Compound I per ml of stable formulation may vary from 1 mg to about 50 mg or even more, depending on the particular compound. We prefer to use at least 1 mg/ml and up to about 40 mg/ml.
The pH of the final composition should be in the range of from about 4 to about 7, and preferably is from about 5.0 to about 6.7. Most preferably, the pH is within the range of from about 6.0 to about 6.5.
~ 7 ~
Optionally, about 9 mg/ml of the preservative benzyl alcohol may be added to the formulation. This is partlcularly desirable if the formulation is packaged in multiple dose form.
The pharmaceutically acceptable acid addition salts of the compounds of Formula I may be derived from any of the acids commonly used in the pharmaceutical art. Preferred salts are the sulfate, maleate, tartrate, citrate and hydrochloride, with the hydrochloride being the most preferred.
The hydroxylic stabilizing compounds utilized herein, such as ethanol, propylene glycol, glycerol and mannitol, all lower the dielectric constant of the formulations.
Although we believe that the stabilizing effect is due, at least partially, to the lowered dielectric constant of the -formulations, we do not intend to limit ourselves to any particular theory.
The dosage of the compounds of Formula I depend on the particular active ingredient, the age, weight and general health of the patient, as well as the severity of the malady, and is within the discretion of the physician. For the prevention of nausea and vomiting associated with emetogenic cancer chemotherapeutic agents, the compounds of Formula I are generally administered at a dosage of from about 1 mg/kg to about 50 mg/kg, given several times per day.
7~3 Example 1 Inqredient Amount/ml Compound Ia Hydrochloride 5.~ mg Glycerol 200 mg Sodlum Hydroxide (O.OlN) 65 ~1 Water for Injection q.s. ad 1.00 ml Procedure for Formulation Into a suitable çompounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approximately 70% of the batch volume of water in the compounding vessel. Quantitatively add the glycerol with continuous stirring until complete mixing is achieved.
Add the active ingredient and the sodium hydroxide solution~
Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
_ g _ ' ~q~
Example 2 In~redlent Amount/ml Compound Ia Hydrochloride 5.51 mg Propylene Glycol 200 mg Sodium Hydroxide ~O.01 N) 70 ~1 Water for Injection q.s. ad1.00 ml Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes, While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approxima~ely 70% of the batch volume of water in the compounding vessel. Quantitatively add the propylene glycol with continuous stirring until complete mixing is achieved. Add the active ingredient and the sodium hydroxide solution. Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 3-Ingredient Amount/ml Compound la Hydrochloride5.51 mg Ethyl Alcohol 200 mg Sodium Hydroxide (O.OlN) 55 ~1 Water for injecticn ~.s. ad 1.00 ml Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approximately 70% of the batch volume of water in the compounding vessel. Quantitatively add the ethyl alcohol with continuous stirring until complete mixing is achieved. Add the active ingredient and the sodium hydroxide solution. ~ring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 4 Ingredient Amount~ml Compound Ia Hydrochloride44.1 mg Glycerol 200 mg Sodium Hydroxide (O.OlN)to pH 6.0-6.2 Water for Injection q.s. ad 1.00 ml l~,tZ7~3 Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approximately 70% of the batch volume of water in the compounding vessel. Quantitatively add the glycerol with continuous stirring untll complete mixing is achieved. Add the active ingredient and the sodium hydroxide solution.
Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 5 Ingredient Amount/ml Compound Ia Hydrochloride 11.0 mg Glycerol 350 mg Sodium Hydroxide (O.OlN) to pH 6.0-6.2 Water for Injection q.s. ad 1.00 ml Procedure for Formulation Into a suitable compounding vessel add an excess of the batch volume of Water for Injection. Heat to boiling and allow the water to boil for ten minutes. While cooling, cover the container, bubble nitrogen through the water and keep a jet of nitrogen on top. Withdraw part of the water, leaving approxima~ely 70% of the batch volume of water in the compounding vessel. Quantitatively add the glycerol with continuous stirring until complete mixing is achieved.
27(~3 Add the active ingredient and the sodium hydroxide solution.
Bring the solution to final volume, filter it through a sterilizing membrane and fill into sterile containers with a nitrogen overlay.
Example 6 Ingredient Amount/ml Compound Ia Hydrochloride 1.1025 mg Glycerol 100.0 mg Benzyl Alcohol 9.0 mg Sodium Hydroxide (l.ON) to pH 6.3+0.2 Water for Injection q.s. ad 1.00 ml Example 7 In~redient Amount/ml Compound Ia Hydrochloride 11.025 mg Glycerol 100.0 mg Benzyl Alcohol 9.0 mg Sodium Hydroxide (l.ON) to pH 6.3+0.2 Water for Injection q.s. ad 1.00 ml Example 8 Ingredient Amount/ml Compound Ia Hydrochloride 27.56 mg Glycerol 100.0 mg Benzyl ~lcohol .9.0 mg Sodium Hydroxide (l.ON) to pH 6.3+0.2 Water for Injection q.s. ad 1.00 ml Procedure_f r Formulation of ExamPles 6L 7 and 8 In a suitable vessel, collect 80% of the required amount of Water for Injection and overlay with nitrogen.
While stirring, add and dissolve the Glycerol, Benzyl Alcohol and Compound Ia. Agitate to ensure homogeniety and continuously overlay with Nitrogen NF. Adjust the pH of the solution to 6.3 ~ 0.2 by addition of lN Sodium Hydroxide Solution. Bring the solution to the desired batch volume with Water for Injection, and stir to ensure complete dissolution. Aseptically filter the solution using a sterilized membrane filter, and collect the filtrate in a sterilized receiving vessel. Fill the solution into sterilized ampules, overlay with nitrogen and seal the ampules.
Tables 3 and 4, below, provide stability data for some of the stable injectable formulations of the present invention.
Table 3 Stabilit~ of Com~ound Ia (5mq~ml) in Ethanol-Water Mixtures at 56C
Ethanol/Water Calculated % Remaining % Remaining ~v/v) Dielectric(4 weeks)(8 weeks) Constant .
0/100 78.5 94.9 89.4 25/75 64.9 98.7 97.-5 50/50 51.4 99.5 99.1 75/25 37.8 99.6 99.6 `
Table 4 Stability of ComPound Ia (5mg/ml) in Pro~Ylene Glvcol-Water and Glvcerol-Water at 56C
Solvent Calculated% Remaining %Remaining Dielectric (4 weeks)(8 weeks) Constant -Water 78.5 94.9 88.1 25% (w/v) 67.3 97.7 96.8 Propylene Glycol 5% (w/v) Glycerol 76.3 95.1 90.9 15% ~w/v) Glycerol 71.8 96.. 5 94.2 25% (w/v) Glycerol 71.4 96.8 95.3
Claims (14)
1. A composition comprising a stable, injectable, aqueous solution of an antiemetic agent of the formula I
wherein R1, R2 and R3 each are independently hydrogen or methyl, and R4 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or, when R3 is hydrogen, R4 may be phenyl, or a non-toxic, pharmaceutically acceptable acid addition salt thereof, containing as stabilizing agent a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the dielectric constant of the solution.
wherein R1, R2 and R3 each are independently hydrogen or methyl, and R4 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or, when R3 is hydrogen, R4 may be phenyl, or a non-toxic, pharmaceutically acceptable acid addition salt thereof, containing as stabilizing agent a pharmaceutically acceptable, water-miscible, hydroxylic organic solvent or water-soluble polyhydric alcohol or sugar which decreases the dielectric constant of the solution.
2. A composition of Claim 1 wherein the stabilizing agent is selected from ethanol, propylene glycol, glycerol and mannitol, and is present in an amount of from about 5% to about 30% (w/v).
3. A composition of Claim 2 wherein the compound of Formula I is present in an amount of from about .1% to about
4% (w/v).
4. A composition of Claim 3 wherein the pH is in the range of from about 5.0 to about 6.7.
4. A composition of Claim 3 wherein the pH is in the range of from about 5.0 to about 6.7.
5. A composition of Claim 4 wherein the compound of Formula I is 4-amino-2-(2-butanon-3-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide.
6. A composition of Claim 5 wherein the stabilizing agent is ethanol.
7. A composition of Claim 5 wherein the stabilizing agent is propylene glycol.
8. A composition of Claim 5 wherein the stabilizing agent is glycerol.
9. A composition of Claim 8 wherein the compound of Formula I is present as the hydrochloride salt and the pH is in the range of from about 6.0 to about 6.5.
10. A composition of Claim 9 wherein the glycerol is present in an amount of about 10% (w/v).
11. A composition of Claim 4 which additionally contains benzyl alcohol as a preservative.
12. A composition of Claim 10 which additionally contains about 9 mg of benzyl alcohol per ml as a preservative.
13. A process for preparing a composition comprising a stable, injectable, aqueous solution of an antiemetic agent of the formula I
wherein R1, R2 and R3 each are independently hydrogen or methyl, and R4 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or, when R3 is hydrogen, R4 may be phenyl, or a non-toxic, pharmaceutically acceptable acid addition salt thereof, which comprises:
(a) in a suitable compounding vessel, boiling a quantity of water in excess of a predetermined final batch volume;
(b) bubbling nitrogen through and over the water in the covered compounding vessel until the water has cooled;
(c) withrawing a portion of the water from the compounding vessel to leave approximately 70% of said final batch volume, and mixing therewith from about 5% to about 70% (w/v) of a hydroxylic stabilizer selected from the group consisting of ethanol, propylene glycol, glycerol and mannitol; and (d) adding to the mixture a quantity of said antiemetic agent and a quantity of sodium hydroxide solution, and bringing the solution to its final batch volume with said previously withdrawn water, the quantity of said antiemetic agent and said sodium hydroxide solution added being such that said antiemetic agent is present in a concentration from about 1 mg/ml to about 40 mg/ml in a final composition having a pH lying in the range of from about 4 to about 7.
wherein R1, R2 and R3 each are independently hydrogen or methyl, and R4 is hydrogen, a straight or branched chain alkyl group containing from 1 to 4 carbon atoms or, when R3 is hydrogen, R4 may be phenyl, or a non-toxic, pharmaceutically acceptable acid addition salt thereof, which comprises:
(a) in a suitable compounding vessel, boiling a quantity of water in excess of a predetermined final batch volume;
(b) bubbling nitrogen through and over the water in the covered compounding vessel until the water has cooled;
(c) withrawing a portion of the water from the compounding vessel to leave approximately 70% of said final batch volume, and mixing therewith from about 5% to about 70% (w/v) of a hydroxylic stabilizer selected from the group consisting of ethanol, propylene glycol, glycerol and mannitol; and (d) adding to the mixture a quantity of said antiemetic agent and a quantity of sodium hydroxide solution, and bringing the solution to its final batch volume with said previously withdrawn water, the quantity of said antiemetic agent and said sodium hydroxide solution added being such that said antiemetic agent is present in a concentration from about 1 mg/ml to about 40 mg/ml in a final composition having a pH lying in the range of from about 4 to about 7.
14. A process for preparing a composition comprising a stable, injectable, aqueous solution of the antiemetic agent, 4-amino-2-(2-butanon-3-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]
benzamide hydrochloride, which comprises:
(a) in a suitable compounding vessel, boiling a quantity of water in excess of a predetermined final batch volume;
(b) bubbling nitrogen through and over the water in the covered compounding vessel until it has cooled;
(c) withdrawing a portion of the water to leave approximately 70% of said final batch volume in the compounding vessel, and mixing therewith from about 5% to about 25% (w/v) of glycerol; and (d) adding to the mixture a quantity of said antiemetic agent and a quantity of sodium hydroxide solution, and bringing the solution to its final batch volume with previously withdrawn water, the quantity of said antiemetic agent and of said sodium hydroxide solution being such that said antiemetic agent is present in a concentration from about 1 mg/ml to about 40 mg/ml in a final composition having a pH in the range of from about 6.0 to about 6.5.
benzamide hydrochloride, which comprises:
(a) in a suitable compounding vessel, boiling a quantity of water in excess of a predetermined final batch volume;
(b) bubbling nitrogen through and over the water in the covered compounding vessel until it has cooled;
(c) withdrawing a portion of the water to leave approximately 70% of said final batch volume in the compounding vessel, and mixing therewith from about 5% to about 25% (w/v) of glycerol; and (d) adding to the mixture a quantity of said antiemetic agent and a quantity of sodium hydroxide solution, and bringing the solution to its final batch volume with previously withdrawn water, the quantity of said antiemetic agent and of said sodium hydroxide solution being such that said antiemetic agent is present in a concentration from about 1 mg/ml to about 40 mg/ml in a final composition having a pH in the range of from about 6.0 to about 6.5.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US84861586A | 1986-04-07 | 1986-04-07 | |
| US848,615 | 1986-04-07 | ||
| US019,733 | 1987-03-10 | ||
| US07/019,733 US4882356A (en) | 1987-03-10 | 1987-03-10 | Stable injectable antiemetic compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1282703C true CA1282703C (en) | 1991-04-09 |
Family
ID=26692535
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000534087A Expired - Fee Related CA1282703C (en) | 1986-04-07 | 1987-04-07 | Stable injectable antiemetic compositions |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0241837B1 (en) |
| KR (1) | KR900002745B1 (en) |
| CN (1) | CN87103415A (en) |
| AT (1) | ATE70716T1 (en) |
| AU (1) | AU597955B2 (en) |
| CA (1) | CA1282703C (en) |
| CS (1) | CS265238B2 (en) |
| DE (1) | DE3775445D1 (en) |
| DK (1) | DK175787A (en) |
| EG (1) | EG18407A (en) |
| ES (1) | ES2038134T3 (en) |
| FI (1) | FI871447A (en) |
| GR (1) | GR3003636T3 (en) |
| HU (1) | HU198622B (en) |
| IL (1) | IL82122A0 (en) |
| NO (1) | NO871434L (en) |
| NZ (1) | NZ219890A (en) |
| PT (1) | PT84635B (en) |
| ZW (1) | ZW6287A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5561161A (en) * | 1994-03-25 | 1996-10-01 | Oxigene, Inc. | Methods of administering and pharmaceutical formulations containing n-substituted benzamides and/or acid addition salts thereof |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2731013C2 (en) * | 1977-07-08 | 1982-07-15 | Lentia Gmbh | Process for the preparation of an aqueous solution for infusion |
| EP0008525A3 (en) * | 1978-08-25 | 1980-05-28 | Beecham Group Plc | Pharmaceutical compositions and process for their preparation |
| JPS599539B2 (en) * | 1979-11-13 | 1984-03-03 | 日本化薬株式会社 | Nitroglycerin aqueous solution and its manufacturing method |
| US4328213A (en) * | 1979-11-28 | 1982-05-04 | Schering Corporation | Stable injectable labetalol formulation |
| GB8412585D0 (en) * | 1984-05-17 | 1984-06-20 | Beecham Group Plc | Composition |
| US4808624A (en) * | 1984-06-28 | 1989-02-28 | Bristol-Myers Company | Pharmacologically active substituted benzamides |
| JPH0710771B2 (en) * | 1984-10-23 | 1995-02-08 | ナステツク フア−マス−テイカル カンパニ−、インコ−ポレイテツド | Novel dosing composition for anti-nausea and anti-emetic drugs |
-
1987
- 1987-04-02 FI FI871447A patent/FI871447A/en not_active Application Discontinuation
- 1987-04-03 ZW ZW62/87A patent/ZW6287A1/en unknown
- 1987-04-06 ES ES198787105073T patent/ES2038134T3/en not_active Expired - Lifetime
- 1987-04-06 EP EP87105073A patent/EP0241837B1/en not_active Expired - Lifetime
- 1987-04-06 NZ NZ219890A patent/NZ219890A/en unknown
- 1987-04-06 KR KR1019870003262A patent/KR900002745B1/en not_active IP Right Cessation
- 1987-04-06 IL IL82122A patent/IL82122A0/en not_active IP Right Cessation
- 1987-04-06 AT AT87105073T patent/ATE70716T1/en not_active IP Right Cessation
- 1987-04-06 DE DE8787105073T patent/DE3775445D1/en not_active Expired - Fee Related
- 1987-04-06 NO NO871434A patent/NO871434L/en unknown
- 1987-04-06 HU HU871472A patent/HU198622B/en not_active IP Right Cessation
- 1987-04-06 CS CS872472A patent/CS265238B2/en unknown
- 1987-04-06 DK DK175787A patent/DK175787A/en not_active Application Discontinuation
- 1987-04-07 CN CN198787103415A patent/CN87103415A/en active Pending
- 1987-04-07 PT PT84635A patent/PT84635B/en not_active IP Right Cessation
- 1987-04-07 EG EG203/87A patent/EG18407A/en active
- 1987-04-07 CA CA000534087A patent/CA1282703C/en not_active Expired - Fee Related
- 1987-04-07 AU AU71159/87A patent/AU597955B2/en not_active Ceased
-
1992
- 1992-01-23 GR GR910401737T patent/GR3003636T3/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO871434L (en) | 1987-10-08 |
| FI871447A0 (en) | 1987-04-02 |
| NO871434D0 (en) | 1987-04-06 |
| EG18407A (en) | 1993-02-28 |
| KR900002745B1 (en) | 1990-04-28 |
| AU597955B2 (en) | 1990-06-14 |
| CN87103415A (en) | 1988-01-20 |
| EP0241837A3 (en) | 1989-05-10 |
| CS265238B2 (en) | 1989-10-13 |
| ZW6287A1 (en) | 1987-09-23 |
| IL82122A0 (en) | 1987-10-30 |
| FI871447A (en) | 1987-10-08 |
| CS247287A2 (en) | 1989-01-12 |
| GR3003636T3 (en) | 1993-03-16 |
| ES2038134T3 (en) | 1993-07-16 |
| PT84635A (en) | 1987-05-01 |
| EP0241837B1 (en) | 1991-12-27 |
| AU7115987A (en) | 1987-10-08 |
| PT84635B (en) | 1989-11-30 |
| KR870009714A (en) | 1987-11-30 |
| DK175787D0 (en) | 1987-04-06 |
| EP0241837A2 (en) | 1987-10-21 |
| ATE70716T1 (en) | 1992-01-15 |
| HU198622B (en) | 1989-11-28 |
| NZ219890A (en) | 1990-07-26 |
| HUT43489A (en) | 1987-11-30 |
| DK175787A (en) | 1987-10-08 |
| DE3775445D1 (en) | 1992-02-06 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP0063367B1 (en) | Acetal stabilized prostaglandin compositions | |
| JP4311369B2 (en) | Stable pharmaceutical composition containing 4,5-epoxymorphinan derivative | |
| CA1216240A (en) | Pharmaceutical composition containing ranitidine | |
| NZ198533A (en) | Soft gelatin capsules containing prostaglandins | |
| US4861786A (en) | Composition for a stable vein compatible injectable solution of torasemide process for the preparation and method of use | |
| EP0179808A1 (en) | Pharmaceutical composition suitable for treatment or prophylaxis of cardiac disorders. | |
| RO113303B1 (en) | Enhanced stability pyroxycam solution | |
| US6664284B2 (en) | Stabilized carvedilol injection solution | |
| US4696814A (en) | Parenteral phenytoin compositions | |
| JPS605567B2 (en) | Oxytetracycline preparation | |
| CA1282703C (en) | Stable injectable antiemetic compositions | |
| US4289783A (en) | Etomidate-containing compositions | |
| US4882356A (en) | Stable injectable antiemetic compositions | |
| US4594243A (en) | Base composition for medicament and pharmaceutical composition for external medication | |
| US6841576B2 (en) | Anti-hypertensive composition and methods of treatment | |
| US4389414A (en) | Prostaglandin compositions | |
| JPH0478612B2 (en) | ||
| US5561154A (en) | Treatment of acute urinary retention | |
| US4032645A (en) | Injectable metronidazole composition | |
| US4301175A (en) | E-Type prostaglandin compositions | |
| EP0533938A1 (en) | Composition for rectal administration of difficultly absorbable peptide | |
| IE63292B1 (en) | Parenteral formulations of 1-diphenylmethyl-4-((2-(4-methylphenyl)-5-methyl-1h-imidazol-4-yl) methyl)piperazine | |
| CA1142434A (en) | Pharmaceutical composition | |
| KR20070076769A (en) | Injection formulation containing amlodipine and preparing method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKLA | Lapsed |